Activated protein C resistance shows an association with pregnancy-induced hypertension

A common mutation in the factor V gene, the Leiden mutation, is the most frequent genetic cause of resistance to activated protein C (APC). Recent studies have shown that the prevalence of APC resistance is associated with severe pregnancy-induced hypertension (PIH). Our objective was to determine whether the factor V Leiden mutation is more prevalent in patients who developed severe PIH than in normotensive pregnant women. In 70 women with a history of severe PIH, of whom 15 had pre-eclampsia, we investigated common coagulation factors as well as APC resistance (factor V related). We found that seven of these 70 women showed low values for APC. Out of these, five were heterozygous and none was homozygous for factor V Leiden mutation. In a control group of normotensive pregnant women we found a 3.0% rate of APC resistance and a 3.0% rate of carriers of the Leiden mutation. These results indicate a significantly higher prevalence of both APC resistance and factor V Leiden mutation in women with severe PIH. Placental infarctions and micro-embolisms are considered to be one of the principle pathophysiological changes in severe PIH. Our results suggest that APC resistance is a risk factor for severe PIH, in addition to its well-known role in macrothrombo-embolism.     

Frequency and significance of preterm delivery in twin pregnancies.

OBJECTIVE: We investigated the frequency of preterm delivery and its influence on the neonatal outcome in twin pregnancies at a perinatal center. Are there differences in the course of twin pregnancies with preterm or term delivery? METHOD: A retrospective investigation was carried out at the Department of Obstetrics on 502 twin pregnancies and deliveries between 1978 and 1993. Pregnancy history and clinical parameters were compared among preterm (<37+0 weeks) and term deliveries. RESULT: Median duration of all twin pregnancies was 36+3 weeks of gestation. In the preterm group, preterm labor was more frequent, both, the first and the second neonate had lower birth weight and were more often admitted to the neonatal intensive care unit (NICU) where they stayed longer than full-term neonates needing intensive care. Perinatal deaths occurred only in the preterm group. CONCLUSIONS: The incidence of preterm delivery is significantly elevated in twin pregnancies and consequently the incidence of low- and very-low-birth-weight-infants and perinatal mortality. Preterm delivery is the main reason why twin pregnancies are at a higher risk for an adverse neonatal outcome and thereby cause considerable costs.     

Internal jugular vein thrombosis caused by resistance to activated protein C as a complication of ovarian hyperstimulation after in-vitro fertilization

We present a case of a 24 year old woman who became pregnant(twins) after human menopausal gonadotrophin (HMG)-induced ovarianstimulation, in-vitro fertilization (IVF) and subsequent embryotransfer. She developed a right internal jugular vein thrombosisas a complication of severe ovarian hyperstimulation syndrome(OHSS) 28 days after embryo transfer. The thrombosis developedin spite of anticoagulation with low-dose heparin. Later a resistanceto activated protein C (APC) or Dahlbäck disease was diagnosed.Due to a new test procedure (accelerin inactivation test), thediagnosis was possible even under anti-coagulation treatment.The coincidence of hyperstimulation and internal jugular veinthrombosis with the concurrent diagnosis of resistance to APChas not been published previously. The benefit of general screeningfor resistance to APC before admission to the IVF programmeshould be weighed. Targeted selection of a group of high-riskwomen would therefore be made possible.     

Clomiphene citrate as a possible cause of a psychotic reaction during infertility treatment

Secondary side-effects often occur in women undergoing hormonal stimulation treatment with clomiphene citrate. In general 10.4% of women experience hot flushing, 5.5% have complaints caused by enlargement of the ovaries and 3.5% experience central nervous symptoms (nervousness, sleeplessness, headaches, visual disturbances, vertigo). During ovarian stimulation with clomiphene citrate for in-vitro fertilization, a 32 year old patient developed psychotic symptoms, commencing 3 days after initiation of treatment. Hospitalization in the psychiatric ward became necessary when severe formal and rational thought disturbances arose together with perceptory and sensory delusions. Under neuroleptic treatment the symptoms improved. Nevertheless, follow-up psychiatric care on an outpatient basis was deemed necessary. The infertility treatment was continued with human menopausal gonadotrophin stimulation. Psychiatric instability occurred neither at this point nor during the 2 year follow-up observation period. Both an exogenous psychosis (ICD F23.9) as well as the exacerbation of an endogenous psychosis (ICD F29) may be considered for the differential diagnosis. The stimulation with clomiphene citrate in connection with the physical and psychic stress of the infertility therapy can be regarded as the trigger factor. For patients with evidence of psychiatric illness in their case history, ovulation- inducing substances such as clomiphene citrate should be implemented with particular care.      

Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor

Immune mechanisms and the renin-angiotensin system are implicated in preeclampsia. We investigated 25 preeclamptic patients and compared them with 12 normotensive pregnant women and 10 pregnant patients with essential hypertension. Antibodies were detected by the chronotropic responses to AT1 receptor-mediated stimulation of cultured neonatal rat cardiomyocytes coupled with receptor-specific antagonists. Immunoglobulin from all preeclamptic patients stimulated the AT1 receptor, whereas immunoglobulin from controls had no effect. The increased autoimmune activity decreased after delivery. Affinity-column purification and anti-human IgG and IgM antibody exposure implicated an IgG antibody directed at the AT1 receptor. Peptides corresponding to sites on the AT1 receptor's second extracellular loop abolished the stimulatory effect. Western blotting with purified patient IgG and a commercially obtained AT1 receptor antibody produced bands of identical molecular weight. Furthermore, confocal microscopy of vascular smooth muscle cells showed colocalization of purified patient IgG and AT1 receptor antibody. The protein kinase C (PKC) inhibitor calphostin C prevented the stimulatory effect. Our results suggest that preeclamptic patients develop stimulatory autoantibodies against the second extracellular AT1 receptor loop. The effect appears to be PKC-mediated. These novel autoantibodies may participate in the angiotensin II-induced vascular lesions in these patients.